Epithelial-mesenchymal interactions are key for organ morphogenesis, tissue homeostasis and carcinogenesis. Notch signaling is an important form of cell-cell communication with an essential pro- differentiation function in the epithelial compartment of the skin. Our main goal is to explore the role of this pathway in the underlying mesenchyme. We will test the following specific hypotheses: 1) Notch/CSL signaling in dermal fibroblasts may play an essential function in intrinsic control of proliferation potential versus senescence. We will expand on our preliminary findings that deletion of the CSL/RBP-J: gene, the key effector of Notch signaling, results in cell senescence and assess to what extent the Notch1 and/or Notch2 genes are involved. We will explore the underlying mechanisms and assess the significance of the findings for control of dermal aging in vivo. 2) Notch/CSL signaling in dermal cells may be involved in control of keratinocyte proliferation and tumor formation in the overlying epidermis. We will expand on our initial findings that mice with mesenchymal deletion of the CSL/RBP- J: gene exhibit epidermal hyperplasia followed by spontaneous multifocal keratinocyte tumor formation, and test whether these mice have also increased susceptibility to UVB-induced carcinogenesis. We will further explore the underlying mechanisms focusing, in particular, on specific diffusible factor(s) that are under Notch/CSL control in dermal fibroblasts and mitogenic for keratinocytes. 3) Mesenchymal Notch/CSL may play a similar role in human skin. We will assess the consequences of suppression of Notch/CSL signaling on senescence control mechanisms of human dermal fibroblasts and on the capability of these cells to affect proliferation and tumor formation of neighboring keratinocytes. By analysis of clinical samples, we will assess to what extent premalignant versus malignant keratinocytic lesions are linked to down-modulation of mesenchymal Notch signaling and associated molecular and cellular events. We will further investigate whether endogenous Notch signaling in the dermis of human skin is down-modulated as a consequence of UV exposure, a major etiological agent of aging and cancer. PUBLIC HEALTH RELEVANCE: Notch signaling is an important form of cell-cell communication with an essential role in development, tissue homeostasis and cancer development. Our main working hypothesis is that this pathway plays an essential role in the mesenchymal compartment of the skin, with an impact on dermal fibroblast senescence and dermal aging- associated changes, as well as on paracrine control of keratinocyte proliferation and tumor development.)